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J. Biol. Chem., Vol. 282, Issue 44, 32053-32064, November 2, 2007

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The DNA Damage Response Mediator MDC1 Directly Interacts with the Anaphase-promoting Complex/Cyclosome^*

Gideon Coster, Zvi Hayouka, Liron Argaman, Carmit Strauss, Assaf Friedler, Michael Brandeis, and Michal Goldberg¹

From the Department of Genetics, Alexander Silberman Institute of Life Sciences and Department of Organic Chemistry, Hebrew University of Jerusalem, Jerusalem 91904, Israel

MDC1 (NFBD1), a mediator of the cellular response to DNA damage, plays an important role in checkpoint activation and DNA repair. Here we identified a cross-talk between the DNA damage response and cell cycle regulation. We discovered that MDC1 binds the anaphase-promoting complex/cyclosome (APC/C), an E3 ubiquitin ligase that controls the cell cycle. The interaction is direct and is mediated by the tandem BRCA1 C-terminal domains of MDC1 and the C terminus of the Cdc27 (APC3) subunit of the APC/C. It requires the phosphorylation of Cdc27 and is enhanced after induction of DNA damage. We show that the tandem BRCA1 C-terminal domains of MDC1, known to directly bind the phosphorylated form of histone H2AX (-H2AX), also bind the APC/C by the same mechanism, as phosphopeptides that correspond to the C termini of -H2AX and Cdc27 competed with each other for the binding to MDC1. Our results reveal a link between the cellular response to DNA damage and cell cycle regulation, suggesting that MDC1, known to have a role in checkpoint regulation, executes part of this role by binding the APC/C.

Received for publication, July 18, 2007 , and in revised form, September 6, 2007.

^* This research was supported by Israel Science Foundation (ISF) Grant 619/04 and Association for International Cancer Research (AICR) Grant 06-257 (to M. G.), by ISF Grant 598/02 and AICR Grant 05-012 (to M. B.), and by a Bikura grant from the ISF and a Human Frontier Science Program Career Development Award (to A. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Genetics, Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem 91904, Israel. Tel.: 972-2-6586452; Fax: 972-2-6586975; E-mail: goldbergm{at}vms.huji.ac.il.

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